Jay E. Menitove, M.D. President/CEO and Medical Director

Keeping the Focus of

Transfusion Medicine

on Patient Care

April 30, 2013

Heart of America Association of Blood Banks

Financial Relationships

Slide 2

No relevant financial

relationships with any

commercial interests

Slide 3

6,4

00

9,9

54

11,4

68

11,9

82

12,1

59

11,6

10

11,5

32

11,3

07

11,1

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11,5

17 12,3

89

13,8

98

14,1

82

14,6

50

15,0

14

6,000

7,000

8,000

9,000

10,000

11,000

12,000

13,000

14,000

15,000

1971 1980 1982 1984 1986 1988 1989 1992 1994 1997 1999 2001 2004 2006 2008

Millio

ns

Year • Surgenor HEJM 1990; 322:1646

• Wallace Transfusion 1995; 35: 802

• Wallace Transfusion 1998; 38: 625

• NBDRC 1997, 1999, 2002

• Nationwide Blood Collection and Utilization Survey 2005, 2007, 2009

Blood Utilization – United States

Slide 4

2006 2007 2008 2009 2010 2011 2012 est

KC 43.6 43.9 45.3 43.5 39.8 38.2 35.6

US 48.9 49.4

2006 2007 2008 2009 2010 2011 2012 est

KC 43.6 43.9 45.3 43.5 39.8 38.2 35.6

US 48.9 49.4

30

32

34

36

38

40

42

44

46

48

50

Units Transfused per 1,000 Population

Units Transfused per 1,000 Population

85,403 86,862 90,630 87,802 81,160 78,383 73,132

Blood Utilization Patterns

Slide 5

Hence, in my career, two significant downturns in

transfusion utilization.

• Different scenarios / causes

Lessons to be learned?

• Past is prologue?

Four perspectives:

• Patients

• Clinicians

• Hospitals / Health Care Institutions

• Transfusion Medicine Specialists

1980’s – 90’s

Slide 6

Patients:

• Transfusion associated - HIV

• Autologous transfusions

• “Dread fear” of transfusions

Autologous Blood Collection/Transfusion

Slide 7

1980 1982 1984 1986 1987 1989 1992 1994 1997 1999 2001 2004 2006 2008

Collected 28,000 28,000 58,000 200,000 397,000 770,000 1,117,0 750,000 643,000 651,000 619,000 458,000 335,000 253,000

Transfused 0 0 0 0 0 356,000 566,000 482,000 420,000 367,000 359,000 270,000 189,000 159,000

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

Collected

Transfused

Slide 8

Slovic P. Perception of Risk. Science 1987: 236: 280-5

Slide 9

Slovic P. Perception of Risk. Science 1987: 236: 280-5

1980’s – 90’s

Slide 10

Clinicians:

• Consensus Conferences

• Transfusion Guidelines

• Assure transfusions given when

benefit > risk

NIH Consensus Development Conference – June 1988

Slide 11

Hb values > 10 g/dL - rarely require peri-op transfusion

Hb values < 7 g/dL - frequently require red cell transfusion

• Decision to Transfuse

– Depends on clinical assessment aided by lab data

o Arterial oxygenation

o Mixed venous oxygen tension

o Cardiac output

o Oxygen extraction ratio

o Blood volume

•JAMA 1988; 260:2700-2703

•Transfusion Medicine Reviews 1988; 3:63-68

Clinical Studies in Anemia

Slide 12

Transfusion Requirements in Critical Care (TRICC)

RCT critically ill Canadian ICU patients at 25 hospitals

Restrictive Liberal

N 418 patients 420

Hb Trigger 7.0 g/dL 10.0

Maintenance Hb 7-9 g/dL 10-12

Leuko Reduction No No

RBC txf’d 2.6 units 5.6 p=0.01

No txf p randomization 33% 0% p<0.01

Primary Outcome

Death within 30 days 18.7% 23.3% p=0.11

Cardiac events (pulmonary edema, M.I.) 13.2% 21.0% p<0.001

Hebert PC, et al. N Engl J Med 1999; 340:409

Clinical Studies in Anemia

Slide 13

Transfusion Requirements in Critical Care (TRICC) - continued

RCT, critically ill Canadian ICU patients at 25 hospitals

Sub-group analysis – 30 day mortality

Restrictive Liberal

APACHE II scores <20 8.7% 16.1% p<0.03

Age <55 years 5.77% 13.07% p=0.02

Conclusion: 7.0 g/dL threshold (7-9 g/dL maintenance) - effective

(continued)

FOCUS

Slide 14 Carson JL, et al. NEJM 2011; 365:2453

FOCUS (Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair)

Liberal vs. Restrictive Transfusion Trigger Trial – 10 g/dL vs. 8 g/dL or symptoms

– High risk patients (n = 2,016 patients; greater than 50 years old; H/O cardiovascular disease; Hb < 10 g/dL post surgery)

– Hip surgery (2004-2009)

– 47 clinical sites

– Randomized, controlled clinical trial

Primary Outcome – Death at 60 days

– Inability to walk across a room without assistance at 60 days

FOCUS

Slide 15 Carson JL, et al. NEJM 2011; 365:2453

Strategy Liberal Restrictive

N 1007 1009

Age (years) 81.8 81.5

Cardiovascular Disease 63.3% 62.5%

Hypertension 82.2% 81.7%

DM 25.1% 25.5%

Hip Fracture:

Femoral Neck 43.0% 41.9%

Intertrochanter 51.0% 51.8%

Hb (g/dL):

Before Transfusion 9.2 7.9

Symptoms leading to transfusion: tachycardia or hypotension 4.3% 12.2%

Leukocyte reduced RBC 90.2% 88.6%

Transfusion after randomization:

0 3.3% 59.0%

1 41.9% 24.4%

2 34.5% 12.6%

- p = significant

FOCUS

Slide 16

(continued)

Outcomes Liberal Restrictive

Death or inability to walk 60 days 35.2% 34.7% p = 0.90

Death 30 days 5.2% 4.3% p = NS

Death 60 days 7.6% 6.6% p = NS

O.R. primary outcomes: 1.01

Men 1.45 p = 0.03

Women 0.91 p = NS

Function & Symptom Scale:

In hospital myocardial infarction 2.3% 3.8% p = NS

CXR Infiltrate 6.0% 4.8% p = NS

Wound infection 1.4% 0.8% p = NS

Stroke or TIA 0.8% 0.3% p = NS

Death: M.I., pneumonia 8.9% 8.9% p = NS

Randomization to discharge (days) 3.67 3.97 p = NS

No difference in mortality rates: transfusion vs. non-transfusion

Conclusion: Reasonable to withhold transfusion in absence of symptoms of anemia or decline < 8g/dL - even in elderly patients with underlying cardiovascular disease or risk factors

Carson JL, et al. NEJM 2011; 365:2453

1980’s – 90’s

Slide 17

Hospitals / Health Care Institutions

• Risk Mitigation

• Informed consent

• Transfusion Committee Utilization Review

Slide 18

1980’s – 90’s

Transfusion Medicine Specialists

• Zero Risk

o Product Safety

− Infectious Disease Testing

− Leukocyte reduction

o Adherence to FDA regulations in:

− Current Good Manufacturing Practices (cGMP)

− Standardization

Slide 19

Slide 20

Slide 21

Slide 22

Slide 23

Slide 24

Slide 25

Slide 26

Slide 27

Slide 28

Slide 29

Transfusion Medicine Specialists

• Good Laboratory Practice

• Product Safety > Recipient Safety

o Infectious disease testing

• Adherence to FDA regulations

o Current Good Manufacturing Practices

o Standardization

o Zero Risk

• Busch Transfusion 2006

Risk Reduction 1980’s – 90’s

Transfusion Medicine 1980’ - 90’s

Slide 30

Consensus Conference and first RCT

Current Good Manufacturing Practices

Good Laboratory Practices

Blood Supply Safety = enhanced

Zero risk

• Multiple infectious disease tests

− NAT in addition to EIA tests to reduce “window period”

donations i.e. donations made between serologic and RNA/DNA

detection

o HIV: 11 days (22 11 days)

o HCV: 63 days (70 10-25 days)

o HBV: 29 days (69 40 days)

Missouri Hospitals Patient Discharges

Slide 31

875,000

885,000

895,000

905,000

915,000

925,000

935,000

945,000

2006 2007 2008 2009 2010 2011 2012

MO Hospitals Patients Discharged

Kansas Hospitals Patient Discharges

Slide 32

300,000

305,000

310,000

315,000

320,000

325,000

330,000

335,000

340,000

345,000

350,000

2006 2007 2008 2009 2010 2011 2012

KS Hospitals Patients Discharged

Slide 33

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

2006 2007 2008 2009 2010 2011 2012

RBCs Billed - Units per Discharge

1980’s – 90’s

Slide 34

Unemployment 8.2 % in Kansas City

• Widespread concern about job stability

• ?Fewer donors at mobiles

• ? Fewer patients with insurance

“Bad economy leads patients to put off surgery, or rush

it” NY Times – March 13, 2009

• Hip surgeries down 45%

• Patients admitted to hospitals are sicker

• Healthcare employment increasing

Economic Impact 2009

2000’s

Slide 35

Patients:

• Great Recession

• Elective surgery procedure delayed

− 10% of blood utilization

Slide 36

Clinicians:

• Adoptions of TRICC findings

• FOCUS results

• Pediatric/Low Birth Weight Studies

• Patient Blood Management Programs

− Less is more

2000’S

Transfusion Requirements in Pediatric Intensive Care (TRIPICU)

Slide 37

Hb < 7 g/dl (restrictive) versus Hb < 9.5 g/dl (liberal)

N= 320 and N= 317

Stable ICU Patients

Leukocyte-reduced RBC

Not blinded

Primary outcome: Multiple-organ-dysfunction syndrome (MODS)

Restrictive Liberal

Any transfusion 46% 98% P < 0.001

Number of txf 301 542 P < 0.001

Hb before first txf 6.7 8.1 P < 0.001

New/progressive MODS 12% 12%

Conclusion: Restrictive Strategy

• 96% reduction in transfusion exposure

• 44% fewer RBC’s transfused

• no increase in rate of new or progressive MODS in stable critically ill

children (not applicable to premature infants or children with severe

hypoxemia, hemodynamic instability, active blood loss, cyanotic heart

disease)

• Lacroix, et al. NEJM 2007; 356:1609

RBC Transfusion Thresholds in Pediatric Patients with Sepsis

Slide 38

TRIPICU Sub-group Analysis

• Restrictive versus liberal strategy on MODS and adverse

outcomes in critically ill stabilized children with sepsis or septic

shock.

• N = 137 septic patients

• Randomization: N=69 restrictive versus N=68 liberal strategy

• Conclusion: Restrictive strategy may be safe for

hemodynamically stabilized septic patients admitted to the PICU

(most severely ill with sepsis were excluded).

Restrictive Liberal

Received Transfusion 56% 99% P < 0.01

Median txf volume (mL/Kg) 7.6 15.7 p < 0.01

New/progressive MODS 18.8% 19.1% P = NS

• Karam, et al. Pediatric Crit Case Med. 2011; 12=512-518

Extremely Low Birth Weight Infants = Transfusion and Brain Injury

Slide 39

2 RCT’s

Different study designs, study populations, Hb threshold

Percent

Transfused

Number

Transfusions

Death/Severe

Morbidity

Cognitive

Delay

Adverse

Brain Event

Apneic

Episode

PINT/PINT-OS

• Low Threshold 89% 4.9 74.0% 24.4%

• High Threshold 95% 5.7 69.7% 17.6%

• P Value 0.037 0.070 0.25 0.06

Iowa

• Restrictive 90% 2.7 12% 0.84

• Liberal 88% 4.8 0% 0.43

• P Value 1.0 0.006 0.012 0.004

Conclusion: Concern about brain injury; higher Hb

transfusion threshold → neuro-protection

• Kirpalani, et al. J Pediatric 2000; 199:301-7

• Whyte, et al. Pediatrics 2009; 125:207-13

• Bell, et al. Pediatrics 2005; 115:1685-91

2000 - 2013

Slide 40

Hospitals:

• Reimbursement rates restrained

• Lean / Six Sigma

• Cost containment

• Consolidation of hospitals into hospital

systems

Transfusion Costs

Slide 41

Transfusion Costs

Slide 42

• Cost of transfusion in surgical setting

• Activity-based costing study

• Four Hospitals – Three Countries

• Cost of transfusion for surgical procedures higher than previously reported

NEW JERSEY RHODE ISLAND SWITZERLAND AUSTRIA

Cost per Unit $1,183 $726 $611 $522

Consent Requirements 2.5% 2.5%

Outsource In-Hospital Management

- 4% - 4%

Indirect Costs 40% 40% 33% 33%

Blood Management

Bloodless Surgery

• Custer. Transfusion 2010; 50:742

• Shander, et al. Transfusion 2010; 50:753

(continued)

Slide 43

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Slide 44

Transfusion Medicine Specialists

• Transfusion related fatalities

• Patient based innovations

– Match RBC & FFP

– Antibody Registry

– Gift of Smiles Program

– Patient Blood Management – Outcomes

Non-infectious Serious Hazards of Transfusion (NISHOT)

Slide 45 • ABC Blood Bulletin May 2002, Vol 5.

Transfusion Related Fatalities Reported to FDA

Slide 46

Transfusion-Related Fatalities by Complication, FY2007 through FY2011

Reports of TRALI by Implicated Blood Product FY2007 through FY2011

Slide 47

Pump Priming – Heart Surgery in Infants

Slide 48

Fresh whole blood versus reconstituted

whole blood → no advantage*

Decrease donor exposure

• Children’s Mercy Hospital, Kansas City**

• Match RBC’s and FFP from same donor

− Saved 132 exposures for 166 patients (3-month period)

− 81 of 83 open-heart operations – primed with RBC and

FFP from same donor (Jan-Jun, 2004)

* Mou. et al. NEJM 2004; 351:1635

** Hamilton, Menitove. NEJM 2005; 352:731

Antibody Registry

Slide 49

Schwickerwath, et al Transfusion; 50: 1465

Antibody Registry

Slide 50 Schwickerwath, et al Transfusion; 50: 1465

Gift of Smiles

Slide 51

Transfusion by the Numbers: August 2009 – July 2011

ZERO

New

Antibodies

Antigen Matched

20 Patients Sept 2011

941 Donors Gift of Smiles

Program

1.2 Sept 11

1.18 July 11

1.14 Feb 11

Tx: Donor Ratio

Critical Hb Concentration

Slide 52

Jehovah’s Witness’ patients − N = 2,083 − Surgical procedures (13 hospitals, 1981-1994) − Average age = 57 years

Hb Concentration Morbidity Mortality Rate

7.1 – 8.0 g/dL 09.4% 0%

6.1 – 7.0 22.0% 08.9%

5.1 – 6.0 28.6% 09.3%

4.1 – 5.0 57.7% 34.4%

3.1 – 4.0 52.6% 25.0%

2.1 – 3.0 91.7% 54.2%

1.1 – 2.0 100% 100%

Carson, et al. Transfusion 2002; 42:812

Arrhythmia, CHF, M.I., bacteremia, pneumonia, wound infection, death

Hemoglobin Concentration & Time to Death

Slide 53 Tobian N, et al. Transfusion 2009; 49:1395

Re-analysis of Transfusion 2002; 42:812

Hb Concentration Median Days Prior to Death

4.1 – 5.0 g/dL 11

3.1 – 4.0 g/dL 2

2.1 – 3.0 g/dL 2.5

< 2.0 g/dL 1.0

• Temporal latitude exists for treating profound anemia

• Only 10% developed cardiac arrhythmias

• Absence of cardiac sx’s understates poor clinical outcome

RBC Transfusion: AABB Practice Guideline

Slide 54

Recommendation 1:

• Restrictive strategy (7-8 g/dL Hb)

− Hospitalized, stable patients

Recommendation 2:

• Restrictive strategy

− Hospitalized patients with pre-existing cardiovascular disease

− Consolidation of txf for patients with sx’s or Hb < 8 g/dL

Recommendation 3: • No recommendation for hospitalized, hemodynamically stable

patients with acute coronary syndrome

Recommendation 4: • Txf decisions influenced by sx’s as well as Hb

• Carson, et al.

AIM doi:10.1059/0003-4819-156-12-201206190-00429

March 26, 2012

CBC Served Hospitals

Slide 55

Percent of Patients Receiving Transfusions

with Hemoglobin > 10g/dL at Discharge

Local Hospital Blood Utilization

Slide 56

Local Hospital Blood Utilization

Hospital 2009-10 2012

A 48% 17%

B 27% 25%

F 40% 27%

G 38% 50%

CBC Served Hospitals

Slide 57

Adverse effects of RBC transfusion contrasted with other risks.Risk is depicted on a

logarithmic scale.

Carson J L et al. Ann Intern Med doi:10.1059/0003-4819-156-12-

201206190-00429

©2012 by American College of Physicians

Conclusion

Slide 59

Transfusion Medicine • Utilization peaks and valleys

− Reflect safety and efficacy, the economy, and outcomes

• Product safety standards – highest achieved to date

• Next generation

− Less is more – patient outcomes and cost

− Continued focus on patient support

o Cellular therapy including cancer vaccination protocols

oRegenerative medicine

• Paradigm change

− Zero risk Risk based decision making

− Pathogen reduction (chemical, photo/chemical treatments of

red cells, platelets and plasma

Slide 60

Questions

and

Answers

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